Cerebral protection with a xenon-containing gas

ABSTRACT

Xenon or xenon-containing gases and, where appropriate, an NO source are employed as medicament for cerebral protection. Cerebral protection is defined as reducing or preventing impairments of cerebral function of various causes, but especially secondary to perfusion impairments of unclear etiology. The medicament can be used for cerebral protection for the prophylaxis of impairments of cerebral perfusion and for therapy after cerebral disorders have occurred, irrespective of the cause (e.g. cognitive, sensory or motor in nature).

CROSS REFERENCE TO RELATED APPLICATION

The application is a divisional of Ser. No. 10/517,723, filed Dec. 10,2004 now U.S. Pat. No. 7,235,264, all of the details of which areincorporated herein by reference thereto.

The invention relates to a medicament which comprises xenon and, whereappropriate, an NO source.

WO 02/22141 A2 describes the use of xenon or xenon-containing gases asmedicament, in particular cardiovascular agent.

DE 19933704 A1 describes the use of a liquid preparation which comprisesa lipophilic gas such as xenon for neuroprotection andneuroregeneration.

Neuroprotection and neuroregeneration involves the protection and theregeneration of individual nerve cells by acting on NMDA receptors inthe nerve cell. Neuroprotection by modulating the activity of NMDAreceptors is also disclosed in U.S. Pat. No. 6,274,633.

An undersupply of oxygen to the brain leads to damage to the brain.

The invention is based on the object of providing an alternativemedicament, in particular a medicament for the treatment of cerebraldisorders.

It has been found that the oxygen supply in the brain is improved onadministration of xenon or xenon-containing gases, in particular byinhalation. In addition, in this way cognitive, sensory and motorconditions and manifestations secondary to oxygen deficiency in thebrain are alleviated or even cured.

The invention relates to a medicament for cerebral protection having thefeatures described in claim 1.

Cerebral protection is defined as reducing or preventing impairments ofcerebral function of various causes, but especially secondary toperfusion impairments of unclear etiology. The medicament can be usedfor cerebral protection for the prophylaxis of impairments of cerebralperfusion and for therapy after cerebral disorders have occurred,irrespective of the cause (e.g. cognitive, sensory or motor in nature).

The medicament for cerebral protection protects the brain of humans ormammals from damage, in particular from damage associated with oxygendeficiency. It does not act just on single nerve cells but acts on thebrain or on parts. of the brain. The medicament for cerebral protectionacts in particular on the blood vessels in the brain. Available resultsindicate an improvement in cerebral perfusion through administeredxenon. According to preliminary results, xenon acts as vasodilator,especially as capillary vasodilator in the capillary vascular system. Inaddition, according to preliminary results, cerebral autoregulation ismaintained or improved. The oxygen supply in the brain is increased.

The invention thus relates further to the use of xenon or of axenon-containing gas as cerebral vasodilator, preferably as cerebralcapillary vasodilator, in particular as cerebral capillary vasodilatorin the capillary vascular system.

The invention further relates to the use of xenon or of axenon-containing gas to produce a medicament for cerebralvasodilatation, preferably to produce a medicament for cerebralcapillary vasodilatation, in particular to produce a medicament forcerebral capillary vasodilatation in the capillary vascular system.

Xenon or a xenon-containing gas mixture are further used to produce amedicament for the treatment of impairments of blood flow in the brain,to produce a medicament for the treatment of impairment of cerebralperfusion, to produce a medicament for the treatment of cognitiveimpairments, to produce a medicament for cerebral protection, to producea medicament for the prophylaxis and/or therapy of impairments ofcognitive performance, also postoperatively, to produce a medicament forthe treatment of stroke, to produce a medicament for the prophylaxis ofstroke, to produce a medicament for improving the oxygen supply in thebrain, to produce a medicament for the treatment of post-ischemiasyndrome, to produce a medicament for promoting blood flow in the brain.

In addition, xenon or xenon-containing gas mixtures are advantageouslyemployed as medicament for the treatment of states with oxygendeficiency, especially oxygen deficiency in the brain. For example,xenon or xenon-containing gas mixtures are employed in emergencysituations such as the treatment of avalanche victims. Xenon or axenon-containing gas mixture is also used to produce a medicament forimproving the oxygenation of the brain.

Xenon or a xenon-containing gas mixture are further used to produce amedicament for the treatment of cognitive or cerebral dysfunction, inparticular of postoperative cognitive dysfunction after cardiac surgicaloperations, also with use of heart-lung machines (HLM) and cardiacassist systems after general surgical procedures.

Cerebral dysfunctions relate to impairments of the microcirculation, ofoxygen utilization and of metabolic functions. The medicament is thusalso used to treat cerebral disorders such as impairments of themicrocirculation, of oxygen utilization and of metabolic functions.

The medicament effects an increase in the cerebral blood flow and themicrocirculation.

The invention thus further relates to the use of xenon or of axenon-containing gas mixture to produce a medicament for the treatmentof cognitive dysfunction, in particular of postoperative cognitivedysfunction. The invention further relates to the use of xenon or of axenon-containing gas mixture to produce a medicament for the treatmentof cerebral dysfunction.

The medicament for cerebral protection and the indications mentionedcomprises xenon or a xenon-containing gas mixture. It preferablyconsists of gaseous xenon or a xenon-containing gas mixture. Themedicament consists for example of xenon gas, a gas mixture of xenon andoxygen or a gas mixture of xenon, oxygen and an inert gas.

The medicament for cerebral protection and the indications mentioned(referred to as the medicament for short) is preferably gaseous, inparticular it contains no solid or liquid constituents onadministration, and is thus preferably in the form of a pure gas phaseon administration. The medicament for cerebral protection and theindications mentioned is preferably administered by inhalation throughthe lungs. The medicament is also administered by means of a heart-lungmachine. The medicament is preferably used for treating humans.

The medicament for cerebral protection and the indications mentioned isusually provided as pure gaseous xenon. It may also be provided as gasmixture. The medicament is usually employed as a gas mixture whichmaintains respiration and which comprises xenon and oxygen. Such gasmixtures are employed for example in emergency medicine, wheregas-mixing or gas-metering devices are too complicated for mobile use.

Gaseous xenon or xenon-containing gas mixtures are particularlyadvantageously employed for prophylaxis. Prophylactic administration ofxenon or xenon-containing gas mixtures takes place for examplepreoperatively, intraoperatively or postoperatively.

The provided medicament for cerebral protection and the indicationsmentioned, or the medicament produced directly on use, in particular inthe direct vicinity of the patient, is for example a gas mixture whichcomprises from 1 to 80% by volume (based on standard conditions, i.e.20° C., 1 bar absolute) xenon (e.g. remainder oxygen). The medicamentwhich is administered to the patient comprises xenon inpharmacologically or therapeutically effective amount, in particular insubanesthetically or anesthetically effective amount. A medicament withxenon in subanesthetically effective amount is advantageous.Subanesthetically effective (subanesthetic) amounts of xenon mean thoseamounts or concentrations of xenon which are insufficient for generalanesthesia. These are in general amounts of up to 70% by volume xenon,preferably up to 65% by volume, particularly preferably up to 60% byvolume, in particular up to 50% by volume xenon. Pure xenon isaccordingly metered into the patient's respiratory gas in the statedconcentrations. This means that the respiratory gas supplied to thepatient comprises for example from 5 to 60% by volume, 5 to 50% byvolume, 5 to 40% by volume, 5 to 30% by volume or 5 to 20% by volumexenon. In special cases, e.g. for prophylaxis, especially duringprolonged ventilation, a dosage of xenon in the respiratory gas with alow concentration, for example 1 to 35% by volume, 5 to 25% by volume or5 to 20% by volume xenon in the respiratory gas, may be advantageous.

The medicaments, in particular gaseous medicaments, preferably comprisebesides xenon one or more gases or substances which are gaseous at bodytemperature under atmospheric pressure. Examples of gas mixtures whichcan be used are xenon-oxygen gas mixtures or gas mixtures of xenon andone or more inert gases such as nitrogen or a rare gas or xenon-oxygeninert gas gas mixtures. Admixture of a gas to the xenon may be veryadvantageous if it is intended to introduce little xenon into the body.

Examples of gases or gas mixtures employed as medicament for cerebralprotection: 1.) 100% by volume xenon; 2.) 70% by volume xenon/30% byvolume oxygen; 3.) 65% by volume xenon/30% by volume oxygen/5% by volumenitrogen; 4.) 65% by volume xenon/35% by volume oxygen; 5.) 60% byvolume xenon/30% by volume oxygen 10% by volume nitrogen; 6.) 60% byvolume xenon/35% by volume oxygen/5% by volume nitrogen; 7.) 60% byvolume xenon/40% by volume oxygen; 8.) 55% by volume xenon/25% by volumeoxygen/20% by volume nitrogen; 9.) 55% by volume xenon/30% by volumeoxygen/15% by volume nitrogen; 10.) 55% by volume xenon/35% by volumeoxygen/10% by volume nitrogen; 11.) 55% by volume xenon/40% by volumeoxygen/5% by volume nitrogen; 12.) 55% by volume xenon/45% by volumeoxygen; 13.) 50% by volume xenon/50% by volume oxygen; 14.) 50% byvolume xenon/45% by volume oxygen/5% by volume nitrogen; 15.) 50% byvolume xenon/40% by volume oxygen/10% by volume nitrogen; 16.) 50% byvolume xenon/30% by volume oxygen/20% by volume nitrogen; 17.) 50% byvolume xenon/25% by volume oxygen/25% by volume nitrogen; 18.) 45% byvolume xenon/55% by volume oxygen; 19.) 45% by volume xenon/50% byvolume oxygen/5% by volume nitrogen; 20.) 45% by volume xenon/45% byvolume oxygen/10% by volume nitrogen; 21.) 45% by volume xenon/40% byvolume oxygen/15% by volume nitrogen; 22.) 45% by volume xenon/35% byvolume oxygen/20% by volume nitrogen; 23.) 45% by volume xenon/30% byvolume oxygen/25% by volume nitrogen; 24.) 45% by volume xenon/30% byvolume oxygen/25% by volume nitrogen; 25.) 40% by volume xenon/30% byvolume oxygen/30% by volume nitrogen; 26.) 40% by volume xenon/50% byvolume oxygen/10% by volume nitrogen; 27.) 35% by volume xenon/25% byvolume oxygen/40% by volume nitrogen; 28.) 35% by volume xenon/65% byvolume oxygen; 29.) 30% by volume xenon/70% by volume oxygen; 30.) 30%by volume xenon/50% by volume oxygen/20% by volume nitrogen; 31.) 30% byvolume xenon/30% by volume oxygen/40% by volume nitrogen; 32.) 20% byvolume xenon/80% by volume oxygen; 33.) 20% by volume xenon/30% byvolume oxygen/50% by volume nitrogen; 34.) 15% by volume xenon/30% byvolume oxygen/55% by volume nitrogen; 35.) 15% by volume xenon/50% byvolume oxygen/35% by volume nitrogen; 36.) 10% by volume xenon/90% byvolume oxygen; 37.) 10% by volume xenon/50% by volume oxygen/40% byvolume nitrogen; 38.) 10% by volume xenon/30% by volume oxygen/60% byvolume nitrogen; 39.) 10% by volume xenon/25% by volume oxygen/65% byvolume nitrogen; 40.) 5% by volume xenon/25% by volume oxygen/70% byvolume nitrogen; 41.) 5% by volume xenon/30% by volume oxygen/65% byvolume nitrogen; 42.) 5% by volume xenon/50% by volume oxygen/45% byvolume nitrogen; 43.) 5% by volume xenon/30% by volume oxygen/65% byvolume nitrogen; 44.) 5% by volume xenon/95% by volume oxygen; 45.) 1%by volume xenon/99% by volume oxygen; 46.) 1% by volume xenon/30% byvolume oxygen/69% by volume nitrogen; 47.) 1% by volume xenon/25% byvolume oxygen/74% by volume nitrogen.

The medicament, especially the medicament for cerebral protection, isparticularly advantageously employed in intensive-care medicine,especially when the medicament must be administered over a prolongedperiod, for example during long-term ventilation. In this case, themedicament has the particular advantage according to the current stateof knowledge of having no side effects because the medicament itself isnot metabolized by the body. Thus, on use of xenon or xenon-containinggases as medicament, no metabolites are formed in the body, and noaccumulation of the medicament in the body occurs.

Xenon is administered, especially during long-term ventilation and forprophylaxis, advantageously in subanesthetically effectiveconcentrations in a breathable gas (respiratory gas). Administration ofbreathable gases with a content of from 5 to 45% by volume xenon,preferably 5 to 40% by volume xenon, is advantageous especially duringlong-term ventilation. The breathable gas during long-term ventilationhas for example a content of from 20 to 30% by volume oxygen, it beingpossible to increase the oxygen content if required at times for exampleto 30 to 95% by volume oxygen. The remaining gas in the breathable gasusually consists of nitrogen or another inert gas.

The employed xenon gas generally has the natural isotope composition.The isotope composition of the xenon may differ from the natural isotopecomposition, in particular on use for diagnostic purposes. The xenon gasis preferably employed in high purity, as usual for medical gases. Thexenon gas is preferably used as pure gas or mixed with other gases toproduce a gaseous medicament for the applications mentioned.

Gaseous xenon (pure xenon) is generally provided as compressed gas incompressed gas containers such as compressed gas cylinders orpressurized cans. It is also possible to provide xenon-containing gasmixtures in compressed gas containers. The gaseous medicament can alsobe provided in a container as liquefied gas or gas mixture or incryogenically solidified form.

The medicament is usually administered using a ventilation machine witha gas-metering unit or with an anesthesia machine. The pharmaceutical isadvantageously produced from the pure gases immediately before use, forexample by mixing xenon, oxygen and, where appropriate, an inert gas(e.g. with the aid of an anesthesia machine) in the direct vicinity ofthe patient.

The medicament is usually administered as dry, moist gas or watervapor-saturated gas to the patient.

It is advantageous further to combine the xenon-containing medicamentwith a medicament which comprises an NO source, preferably for thetreatment or prophylaxis of cerebral disorders, in particular for usefor cerebral protection.

The invention thus further relates to a medicament comprising xenon andan NO source or a xenon-containing gas mixture and an NO source, wherexenon and NO source are present in pharmacologically effectiveconcentration.

The invention further relates to a combination product for simultaneous,separate or sequential use of xenon and an NO source or axenon-containing gas and an NO source.

The invention relates in particular to a medicament consisting of aninhalable medicament comprising xenon or a xenon-containing gas, and amedicament which is administered preferably orally, by inhalation orparenterally and which comprises an NO source, as combination productfor simultaneous, separate or sequential use.

The invention further relates to the use of xenon and of an NO source ora xenon-containing gas and an NO source for the treatment of cerebraldisorders, in particular for cerebral protection.

The invention further relates to the use of xenon and of an NO source ora xenon-containing gas and an NO source to produce a medicament for thetreatment of cerebral disorders, in particular a medicament for cerebralprotection.

The medicament serving as combination product preferably consists of aninhalable medicament comprising xenon or a xenon-containing gas, and ofa medicament which is administered orally, by inhalation (e.g. asaerosol) or parenterally and which comprises an NO source.

A nitric oxide source (NO source) is NO (nitric oxide), an NO-containinggas or gas mixture or, preferably, a substance or preparation whichreleases nitric oxide (NO), stimulates endogenous NO production orinhibits the breakdown of NO in the body. A nitric oxide source are, inparticular, NO-releasing and/or NO-forming compounds.

NO sources and, in particular, NO-releasing compounds are described inDE 691 27 756 T2 (e.g. page 8, line 7, to page 9, end of the secondparagraph, therein), to which reference is hereby made. Examples ofNO-releasing compounds are S-nitroso-N-acetylpienicillamine (SNAP),S-nitrosocysteine, nitroprusside, nitrosoguanidine, glycerol trinitrate,isoamyl nitrite, inorganic nitrite, azide or hydroxylamine. TheNO-releasing compounds are introduced into the lung for example byinhalation as aerosol, as described in DE 691 27 756 T2 and to whichreference is hereby made.

If it is intended to increase the NO level in the brain onadministration of NO-releasing compounds via the blood, this may beprevented by the blood-brain barrier. This problem is circumventedaccording to WO 00/56328 by administering an agent which stimulatesendogenous NO production, such as L-arginine. Substances which increaseendogenous NO production are regarded as NO-forming substances.Substances which stimulate endogenous NO production are advantageouslyemployed in combination with NO-releasing compounds. Preceding orsimultaneous administration of one or more substances stimulatingendogenous NO production improve the ability to deliver the NO-releasingcompounds into the brain, leading to an improved efficacy of theNO-releasing compounds in the brain. One or more substances stimulatingendogenous NO production, one or more NO-releasing compounds and xenonor a xenon-containing gas are thus advantageously administered atseparate times or simultaneously. For example, initially there isadministration of a substance stimulating endogenous NO production and,in a further step, NO-releasing compound and xenon are administered. Itmay also be advantageous to start with administration of xenon byinhalation and, in a further step, to administer the substancestimulating endogenous NO production and an NO-releasing compound,simultaneously or at separate times.

The combination medicament comprises xenon and at least one NO source intherapeutically effective amount. The medicament comprises xenon forexample in subanesthetically or anesthetically effective amount. Thedosage of the substances stimulating endogenous NO production isdescribed for example in WO 00/56328, to which reference is hereby made.The dosage of NO-releasing compounds for administration as aerosol isdescribed in U.S. Pat. No. 5,485,827, to which reference is hereby made.

Medicaments with xenon and an NO source are generally used for thetreatment, prophylaxis or prevention of disorders of the brain,especially for cerebral protection. The invention thus relates tomedicament comprising xenon or a xenon-containing gas and an NO sourceas combination product for simultaneous, separate or sequential use,especially for disorders of the brain in humans.

Xenon or xenon-containing gases and an NO source are used to produce amedicament for the treatment, prophylaxis or prevention of impairmentsof blood flow in the brain, to produce a medicament for the treatment ofimpairment of cerebral perfusion, to produce a medicament for thetreatment of cognitive impairments, to produce a medicament for cerebralprotection, to produce a medicament for the prophylaxis and/or therapyof impairments of cognitive performance, also postoperatively, toproduce a medicament for the treatment of stroke, to produce amedicament for the prophylaxis of stroke, to produce a medicament forimproving the oxygen supply in the brain, to produce a medicament forthe treatment of post-ischemia syndrome, to produce a medicament forpromoting blood flow in the brain.

For example, in a case of stroke the medicament is advantageouslyemployed in the following way. Firstly a xenon-containing gas isadministered, e.g. in subanesthetically and sedatively effective amount.In a next phase of the sequential administration of the medicament,advantageously a gaseous, liquid or solid preparation with an NO source(one or more substances to increase the NO level in the brain) or apreparation with an NO source in combination with xenon or axenon-containing gas is administered.

Xenon or a xenon-containing gas mixture and an NO source are furtherused to produce a medicament for the prophylaxis and/or therapy ofimpairments of cognitive performance, also postoperatively.

The combination medicament is usually employed as combination of onecomponent (e.g. as inhalable medicament) with xenon and of a furthercomponent with an NO source, e.g. a medicament which is administeredparenterally, by inhalation or orally and has at least one NO source.The medicament comprises xenon in a pharmacologically or therapeuticallyeffective amount, e.g. in subanesthetically or anesthetically effectiveamount. The medicament comprises the NO source in a pharmacologically ortherapeutically effective amount.

The combination medicament consists for example of xenon, an inert gasand an is NO source or of xenon, oxygen, an inert gas and an NO source.

1. In a method of treating a patient by administering a medicament tothe patient during the treatment, the improvement being in that themedicament is a xenon preparation which is provided in a form of acombination medicament comprising a pharmacologically effectiveconcentration of xenon selected from the group consisting of gaseousxenon and a xenon containing gas mixture, and a medicament thatcomprises a NO-releasing compound, a substance that stimulatesendogenous NO production wherein said substance is L-arginine,administering the xenon to a patient in a subanesthetic amount whereinthe gaseous xenon or the xenon containing gas mixture administered tothe patient contains no more than 70% bay volume of xenon and when thegaseous xenon or xenon containing gas mixture is metered into thepatient's respiratory gas so that the combined gas supplied to thepatient contains from 5 to 70% by volume xenon, administering themedicament that comprises the NO-releasing compound, the substance thatstimulates endogenous NO production, by inhalation or orally and thecombination medicament is administered to a patient for a treatmentselected from the group consisting of (a) treatment of impairments ofblood flow in the brain, (b) treatment of impairment of cerebralperfusion, (c) cerebral protection, (d) treatment of stroke, (e)improving the oxygen supply in the brain, (f) treatment of post-ischemiasyndrome, (g) promoting blood flow in the brain, and (h) cerebralvasodilation, and selecting a patient in need of one of said treatments(a) to (h).
 2. The method as claimed in claim 1, wherein theNO-releasing compound is selected from the group consisting ofS-nitroso-N-acetylpenicillamine (SNAP), S-nitrosocysteine,nitroprusside, nitrosoguanidine, glycerol trinitrate, isoamyl nitrite,inorganic nitrite, and hydroxylamine.
 3. The method as claimed in claim2, wherein the NO-releasing compound is introduced into the lung byinhalation as aerosol.
 4. The method as claimed in claim 1, wherein thesubstance which stimulates endogenous NO production is employed incombination with the NO-releasing compound.
 5. The method as claimed inclaim 4, wherein the preparation is administered to a patient for atreatment selected from the group consisting of cerebral protection andcerebral vasodilation.
 6. The method as claimed in claim 1, wherein theNO-releasing compound is introduced into the lung by inhalation asaerosol.
 7. The method as claimed in claim 3, wherein the substanceswhich stimulate endogenous NO production is employed in combination withthe NO-releasing compound.
 8. The method as claimed in claim 2, whereinthe substances which stimulate endogenous NO production is employed incombination with the NO-releasing compound.
 9. The method as claimed inclaim 1, wherein the substance which stimulates endogenous NO productionis employed in combination with the NO-releasing compound.
 10. Themethod as claimed in claim 3, wherein the preparation is administered toa patient for a treatment selected from the group consisting of cerebralprotection and cerebral vasodilation.
 11. The method as claimed in claim2, wherein the preparation is administered to a patient for a treatmentselected from the group consisting of cerebral protection and cerebralvasodilation.
 12. The method as claimed in claim 1, wherein thepreparation is administered to a patient for a treatment selected fromthe group consisting of cerebral protection and cerebral vasodilation.